EP0896530B1 - Formes galeniques et leurs utilisations - Google Patents

Formes galeniques et leurs utilisations Download PDF

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Publication number
EP0896530B1
EP0896530B1 EP97907183A EP97907183A EP0896530B1 EP 0896530 B1 EP0896530 B1 EP 0896530B1 EP 97907183 A EP97907183 A EP 97907183A EP 97907183 A EP97907183 A EP 97907183A EP 0896530 B1 EP0896530 B1 EP 0896530B1
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EP
European Patent Office
Prior art keywords
verapamil
dosage form
form according
enantiomers
different
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP97907183A
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German (de)
English (en)
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EP0896530A1 (fr
Inventor
Julian Clive Chiroscience Limited Gilbert
Andrew John Mcglashan Richards
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sosei R&D Ltd
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Arakis Ltd
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Publication of EP0896530A1 publication Critical patent/EP0896530A1/fr
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Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • This invention relates to verapamil and the discovery of novel pharmaceutical dosage forms thereof, and their use.
  • Verapamil (1) is presently in clinical use as a racemate and is used extensively for the treatment of hypertension.
  • the opposite enantiomers of verapamil have different biological activities and different potencies.
  • the pharmacological profile is determined by stereoselectivity of pharmacodynamics and pharmacokinetics.
  • the ( S )-enantiomer levoverapamil
  • the ( R )-enantiomer differs in having greater sodium channel activity (see Bayer, Naunyn Schmiedeberg Arch. Pharmacol.
  • the ( S )-enantiomer may provide a safer treatment than the racemate, with an extended therapeutic window.
  • the ( R )-enantiomer may be of benefit for the reversal of multidrug resistance in cancer chemotherapy (see Eliason, Int. J. Cancer (1990) 46 : 113); in this case hypotensive action by admixture with the ( S )-enantiomer would be undesirable.
  • verapamil is dosed as a racemic mixture both in immediate and controlled-release form, from which each enantiomer is released at the same rate.
  • the pharmacokinetic properties of each enantiomer are different, primarily due to differences in the rates at which they are metabolised. This has the effect that the ratio of the different enantiomers changes with time after initial dosing, which can lead to reduced efficacy of the drug.
  • the actual enantiomeric ratio at any one time is dependent upon a number of factors and is complicated by the fact that different dosage forms provide different enantiomeric ratios.
  • a pharmaceutical dosage form comprises, in one portion thereof, substantially single enantiomer ( R )-verapamil and, in another, separate, portion thereof, substantially single enantiomer ( S )-verapamil, wherein, in use, the different enantiomers are released at different rates from the dosage form.
  • the rates of release of the different enantiomers from the dosage form may be arranged such that their initial ratio, whether this is 50:50 or a non-racemic ratio, is maintained throughout the dosing period.
  • the present invention may also be beneficial if one of the enantiomers of verapamil is found to be responsible for causing an adverse side effect, as by altering the release from the dosage form of that enantiomer a significant reduction in that side effect may be achieved.
  • substantially single enantiomer typically we mean that one enantiomer is in an excess of at least 70% by weight with respect to the other enantiomer, and is preferably in an excess of at least 80%, and more preferably 90%, or higher.
  • a number of different types of dosage form can be envisaged, for administration by a variety of routes, e.g. oral, rectal, transdermal, nasal, and ophthalmic.
  • One type of dosage form comprises a capsule containing two sets of multiparticulates having different release rates, one set containing ( R )-verapamil and the other set containing ( S )-verapamil.
  • the multiparticulates themselves can be made by any of the conventional methods, including extrusion spheronisation, high shear granulation, nonpareil seeds, etc.
  • the rates at which the different enantiomers are released from the multiparticulates can be achieved using any conventional controlled-release mechanism, for instance, matrix (ie. erosion diffusion), coating, or osmotic. Dosage forms of this type are suitable for oral use.
  • Another type of dosage form comprises two tablets, i.e. as a combined product (kit), one tablet containing ( R )-verapamil and the other tablet containing ( S )-verapamil, the two tablets having different release rates.
  • kit a combined product
  • R tablet containing
  • S tablet containing
  • conventional control-release technology can be used to achieve the desired effect.
  • two tablets having different release coatings or matrices may be used, or two osmotic pump tablets having different pumping rates.
  • the tablets can then be administered in sequence, but preferably they are filled into a capsule for dosing simultaneously.
  • Another type of dosage form comprises an osmotic pump tablet comprising two distinct portions, typically two layers, one portion containing and pumping ( R )-verapamil at one rate, and the other portion containing and pumping ( S )-verapamil at another rate.
  • Another type of dosage form comprises a bi-layered tablet, one layer containing ( R )-verapamil and the other layer containing ( S )-verapamil, the two layers having different release rates for their respective enantiomers.
  • R a bi-layered tablet
  • S a layer containing ( S )-verapamil
  • the two layers having different release rates for their respective enantiomers.
  • conventional control-release technology can be used to achieve the desired effect.
  • Another type of dosage form comprises a compressed coat tablet having a core containing one of ( R )- and ( S )-verapamil and, surrounding the core, a shell containing the other of ( R )- and ( S )-verapamil, the core and shell having different release rates for their respective enantiomers.
  • Another type of dosage form comprises a patch for placing adjacent a patient's skin, the patch comprising two distinct portions, one portion containing ( R )-verapamil and the other portion containing ( S )-verapamil, the two portions having different release rates for their respective enantiomers.
  • two separate patches may be used, i.e. as a combined product (kit), one patch containing ( R )-verapamil and the other patch containing ( S )-verapamil, the two patches having different release rates.
  • Another type of dosage form comprises a polymer implant comprising two distinct portions, one portion containing ( R )-verapamil and the other portion containing ( S )-verapamil, the two portions having different release rates for their respective enantiomers.
  • two separate polymer implants may be used, i.e. as a combined product (kit), one implant containing ( R )-verapamil and the other implant containing ( S )-verapamil, the two implants having different release rates.
  • Another type of dosage form comprises an aerosol containing two sets of microparticles having different release rates, one set containing ( R )-verapamil and the other set containing ( S )-verapamil.
  • two separate aerosols may be used, one for each enantiomer, i.e. as a combined product (kit), the microparticles of each aerosol having different release rates.
  • the dosage forms of the present invention may be designed to release either of the enantiomers faster than the other, depending upon the condition to be treated, or the patient type. It may be desirable to maintain a constant ratio of the separate enantiomers at the target tissue over a specified period of time, for instance at least 8 hours a day, preferably at least 12 hours a day, and most preferably 24 hours a day. The ratio maintained may be 50:50, or a non-racemic ratio in which either the amount of ( R )-verapamil is greater than ( S )-verapamil, or vice versa.
  • the ratio of the two enantiomers throughout the treatment period, or at least for a portion of that period.
  • the release rate of either or both enantiomers can be arranged to vary, so that either the relative proportion of ( R )-verapamil or of ( S )-verapamil increases, or decreases, with time. The latter may be achieved, for instance, by using a number of different release coatings for the respective enantiomer.
  • the dosage forms of the invention may be used to beneficial effect in the treatment of conditions for which verapamil is usually administered, such as hypertension, angina, arrhythmia, atherosclerosis, migraine, glaucoma, stroke and cerebral ischaemia, particularly in patients disposed to, or who may be put at risk by exposure to, an adverse side effect.
  • the two enantiomers are effectively dosed separately, it is essential that they are provided in a form that is not harmful to the prospective patient. If they are provided in salt form, both salts should preferably be stable and non-hygroscopic. Most preferably each enantiomer is in the form of its hydrochloride salt.
  • the extrudate was spheronised on a 12 cm diameter spheroniser (Caleva, Sturminister, UK) rotating at a speed of 1800 r.p.m. for 10-15 mins.
  • the pellets produced were dried at 60°C in a fluid bed drier.
  • aqueous dispersion of Surelease (Colorcon Limited, Orpington, UK) was applied to the pellets by spraying in a 3 inch (7.6 cm) Wurster column in a fluid bed coater (model Uni-Glatt, Glatt GmbH, Dresden, Germany) at a rate of 1.61 ml/min. Coatings of different thicknesses were applied as assessed on a weight-gain basis (ie. based on the weight of the uncoated pellets), in the range 1% to 16% gain in weight.
  • Pellets containing ( S )-verapamil were prepared and coated in the same way.
  • the rate of drug release from the coated pellets was determined using a USP paddle method dissolution test procedure, with 1000 ml of distilled water and a paddle speed of 100 rpm at 37°C. Samples were taken continuously and fed through a flow-through cell in a Phillips PU8620 Tablet Dissolution System, to give an automatic absorption record at 230 nm of the dissolution of the drug (% dissolved) with time.
  • Figure 1 is a graph showing the results of the dissolution tests carried out on each set of the coated pellets.
  • TWG means total weight gain, and represents the weight gain of the pellet observed by application of the coating.
  • the graph demonstrates that by altering the coating thickness different enantiomer release rates may be achieved. Therefore, both enantiomers can be formulated together, for sequential or simultaneous use, preferably for simultaneous use in the same formulation, to achieve different plasma concentrations of those enantiomers.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Claims (24)

  1. Forme galénique pharmaceutique comprenant dans l'une de ses parties essentiellement le seul énantiomère (R)-verapamil, et dans une autre de ses parties, séparée, essentiellement le seul énantiomère (S)-verapamil, dans laquelle, en utilisation, les énantiomères différents sont libérés par la forme galénique à des taux différents.
  2. Forme galénique selon la revendication 1, dans laquelle les taux de libération des différents énantiomères sont sélectionnés pour donner un rapport essentiellement constant entre ces énantiomères sur un tissu cible pendant au moins 8 heures d'une journée.
  3. Forme galénique selon la revendication 2, dans laquelle le rapport entre les énantiomères sur le tissu cible est de 50:50.
  4. Forme galénique selon la revendication 2, dans laquelle le rapport entre les énantiomères sur le tissu cible est un rapport non racémique, le (R)-verapamil étant en excès par rapport au verapamil.
  5. Forme galénique selon la revendication 2, dans laquelle le rapport entre les énantiomères sur le tissu cible est un rapport non racémique, le (S)-verapamil étant en excès par rapport au (R)-verapamil.
  6. Forme galénique selon la revendication 1, dans laquelle le taux de libération d'au moins l'un des énantiomères varie au cours du temps.
  7. Forme galénique selon la revendication 6, dans laquelle le taux de libération du (R)-verapamil augmente ou diminue au cours du temps.
  8. Forme galénique selon la revendication 6, dans laquelle le taux de libération du (S)-verapamil augmente ou diminue au cours du temps.
  9. Forme galénique selon la revendication 1, dans laquelle le (R)-verapamil est libéré plus rapidement que le (S)-verapamil.
  10. Forme galénique selon la revendication 1, dans laquelle le (S)-verapamil est libéré plus rapidement que le (R)-verapamil.
  11. Forme galénique selon l'une quelconque des revendications précédentes, qui comprend une gélule contenant une pluralité de premières particules contenant du (R)-verapamil et une pluralité de deuxièmes particules contenant du (S)-verapamil, les premières et les deuxièmes particules présentant des taux de libération différents de leur énantiomère respectif.
  12. Forme galénique selon l'une quelconque des revendications 1 à 10, qui comprend un premier comprimé contenant du (R)-verapamil et un deuxième comprimé contenant du (S)-verapamil, le premier et le deuxième comprimés présentant des taux de libération différents de leur énantiomère respectif.
  13. Forme galénique selon la revendication 12, dans laquelle le premier et le deuxième comprimés sont enfermés dans une gélule.
  14. Forme galénique selon l'une quelconque des revendications 1 à 10, qui comprend un comprimé à pompe osmotique présentant une première partie contenant du (R)-verapamil et une deuxième partie contenant du (S)-verapamil, dans laquelle la première et la deuxième parties présentent des taux de pompage différents de leur énantiomère respectif.
  15. Forme galénique selon l'une quelconque des revendications 1 à 10, qui comprend un comprimé à deux couches, dont une couche contient du (R)-verapamil et l'autre couche contient du (S)-verapamil, les deux couches présentant des taux de libération différents de leur énantiomère respectif.
  16. Forme galénique selon l'une quelconque des revendications 1 à 10, qui comprend un comprimé revêtu présentant un noyau contenant l'un parmi le (R)-verapamil et le (S)-verapamil et, autour du noyau, une enveloppe contenant l'autre parmi le (R)-verapamil et le (S)-verapamil.
  17. Forme galénique selon l'une quelconque des revendications 1 à 10, qui comprend un timbre-réservoir destiné à être placé en contact avec la peau d'un patient, le timbre-réservoir comprenant une première partie contenant du (R)-verapamil, et une deuxième partie contenant du (S)-verapamil, la première et la deuxième parties présentant des taux de libération différents de leur énantiomère respectif.
  18. Forme galénique selon l'une quelconque des revendications 1 à 10, qui comprend deux timbre-réservoirs, chacun destiné à être placé en contact avec la peau d'un patient, un timbre-réservoir contenant du (R)-verapamil et l'autre timbre-réservoir contenant du (S)-verapamil, les deux timbre-réservoirs présentant des taux de libération différents.
  19. Forme galénique selon l'une quelconque des revendications 1 à 10, qui comprend un implant polymère présentant une première partie contenant du (R)-verapamil et une deuxième partie contenant du (S)-verapamil, la première et la deuxième parties présentant des taux de libération différents de leur énantiomère respectif.
  20. Forme galénique selon l'une quelconque des revendications 1 à 10, comprenant deux implants polymères, un implant contenant du (R)-verapamil et l'autre implant contenant du (S)-verapamil, les deux implants présentant des taux de libération différents.
  21. Forme galénique selon l'une quelconque des revendications 1 à 10, qui comprend un aérosol contenant deux ensembles de micro particules présentant des taux de libération différents, un ensemble contenant du (R)-verapamil et l'autre ensemble contenant du (S)-verapamil.
  22. Forme galénique selon l'une quelconque des revendications 1 à 10, qui comprend deux aérosols, l'un contenant des micro particules contenant du (R)-verapamil et l'autre contenant des micro particules contenant du (S)-verapamil, les micro particules des deux aérosols présentant des taux de libération différents de leur énantiomère respectif.
  23. Utilisation essentiellement du seul énantiomère (R)-verapamil et essentiellement du seul énantiomère (S)-verapamil dans la fabrication d'une forme galénique selon l'une quelconque des revendications précédentes, pour le traitement d'un état sélectionné parmi l'hypertension, l'angine, l'arythmie, l'athérosclérose, la migraine, le glaucome, la crise cardiaque et l'ischémie cérébrale.
  24. Utilisation selon la revendication 23, pour le traitement d'un patient présentent une prédisposition à un effet secondaire néfaste, ou qui pourrait être mis en danger par exposition à un effet secondaire néfaste.
EP97907183A 1996-03-11 1997-03-11 Formes galeniques et leurs utilisations Expired - Lifetime EP0896530B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9605074 1996-03-11
GBGB9605074.5A GB9605074D0 (en) 1996-03-11 1996-03-11 Dosage forms and uses
PCT/GB1997/000674 WO1997033570A1 (fr) 1996-03-11 1997-03-11 Formes galeniques et leurs utilisations

Publications (2)

Publication Number Publication Date
EP0896530A1 EP0896530A1 (fr) 1999-02-17
EP0896530B1 true EP0896530B1 (fr) 2002-06-26

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EP97907183A Expired - Lifetime EP0896530B1 (fr) 1996-03-11 1997-03-11 Formes galeniques et leurs utilisations

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US (1) US6267980B1 (fr)
EP (1) EP0896530B1 (fr)
JP (1) JP2000506856A (fr)
AT (1) ATE219665T1 (fr)
AU (1) AU1932997A (fr)
DE (1) DE69713586T2 (fr)
ES (1) ES2179302T3 (fr)
GB (1) GB9605074D0 (fr)
WO (1) WO1997033570A1 (fr)
ZA (1) ZA972094B (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997044025A1 (fr) * 1996-05-23 1997-11-27 G.D. Searle & Co. Compositions pharmaceutiques contenant du verapamil non racemique et procede pour optimiser l'activite pharmaceutique du r- et s-verapamil
US20030170181A1 (en) * 1999-04-06 2003-09-11 Midha Kamal K. Method for preventing abuse of methylphenidate
US20030092765A1 (en) 2001-11-15 2003-05-15 John Kelly Treatment of abnormal increases in gastrointestinal motility with (R)-verapamil
WO2004093816A2 (fr) * 2003-04-22 2004-11-04 Pharmacia Corporation Compositions renfermant un inhibiteur selectif de cyclo-oxygenase-2 et un agent modulateur de calcium pour le traitement de dommages au systeme nerveux central
US20050191245A1 (en) * 2004-02-27 2005-09-01 Adams Christopher P. Nasal administration of calcium channel, blockers for treatment of hypertension and other cardiovascular disorders
MX2009000923A (es) * 2006-08-04 2009-03-09 Agi Therapeutics Res Ltd Metodos para tratar cuando menos una condicion que tiene receptor de mt1, receptor de 5ht2b, y actividad de canal de calcio tipo l.
US9744210B2 (en) * 2012-12-27 2017-08-29 Massachusetts Eye & Ear Infirmary Treatment of rhinosinusitis with P-glycoprotein inhibitors
RU2731918C2 (ru) * 2015-04-14 2020-09-09 Майлстоун Фармасьютикалз Инк. Хорошо растворимые в воде соли фенилалкиламина - быстродействующего блокатора кальциевых каналов и их применение
WO2020198232A1 (fr) 2019-03-25 2020-10-01 Massachusetts Eye And Ear Infirmary Procédés et compositions pour traiter et diagnostiquer des maladies ou des pathologies associées à une inflammation des sinus et de la cavité nasale

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5204116A (en) 1991-05-01 1993-04-20 Alza Corporation Dosage form providing immediate therapy followed by prolonged therapy
DE4319438C1 (de) * 1993-06-11 1994-06-01 Gerd Dr Dr Geislinger Arzneimittel auf der Grundlage von Ketoprofen zur Bekämpfung von Schmerzen und/oder Entzündungen und/oder Fieber an Menschen und Tieren

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JP2000506856A (ja) 2000-06-06
GB9605074D0 (en) 1996-05-08
DE69713586D1 (de) 2002-08-01
EP0896530A1 (fr) 1999-02-17
WO1997033570A1 (fr) 1997-09-18
ZA972094B (en) 1998-03-11
ES2179302T3 (es) 2003-01-16
US6267980B1 (en) 2001-07-31
AU1932997A (en) 1997-10-01
DE69713586T2 (de) 2003-01-09
ATE219665T1 (de) 2002-07-15

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